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. 2025 Aug 28.
doi: 10.1038/s41416-025-03164-5. Online ahead of print.

Primary tumor sidedness and negative hyperselection to modulate anti-EGFR-based maintenance strategies in patients with RAS wild-type metastatic colorectal cancer: individual patient data pooled analysis of two randomized clinical trials

Alexej Ballhausen  1 , Federica Morano  2 , Arndt Stahler  1 , Sara Lonardi  3 , Andreas Jay Kind  1 , Chiara Cremolini  4   5 , Susanna Swoboda  1 , Giovanni Randon  2 , David Horst  6 , Michele Prisciandaro  2 , Annabel Helga Sophie Alig  1 , Chiara Carlotta Pircher  2 , Armin Jarosch  6 , Paola Andena  2 , Annika Kurreck  1 , Anna Alessandra Chiaramonte  2 , Sebastian Stintzing  1   7 , Filippo Pietrantonio  8 , Dominik Paul Modest  9   10 , Alessandra Raimondi  2
Affiliations

Primary tumor sidedness and negative hyperselection to modulate anti-EGFR-based maintenance strategies in patients with RAS wild-type metastatic colorectal cancer: individual patient data pooled analysis of two randomized clinical trials

Alexej Ballhausen et al. Br J Cancer. .

Abstract

Background: Patients with RAS wild-type (WT), left-sided metastatic colorectal cancer (mCRC), negatively hyperselected for anti-EGFR resistance alterations, benefit most from anti-EGFR-based first-line treatment. The predictive impact of these stratification parameters on maintenance strategy efficacy is unclear.

Methods: This pooled analysis included individual patient data from the PanaMa (NCT01991873) and Valentino (NCT02476045) phase 2 trials. Patients with RAS WT mCRC received FOLFOX plus Panitumumab induction therapy followed by maintenance with 5-fluorouracil/leucovorin (5-FU/LV) plus Panitumumab vs. 5-FU/LV monotherapy (PanaMa) or Panitumumab monotherapy (Valentino). Outcomes included progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined primary tumor sidedness (left vs. right) and hyperselection status (negative vs. altered).

Results: Among 607 patients receiving induction, sidedness and hyperselection status were available for 589 and 511 patients, respectively. Left-sided and negative hyperselected tumors were observed in 80.2% and 63.9% of patients, respectively. Panitumumab-based maintenance improved PFS in left-sided, negative hyperselected patients compared to 5-FU/LV alone, with no OS differences. PFS and OS were comparable for Panitumumab alone vs. Panitumumab plus 5-FU/LV.

Conclusion: Tumor sidedness and hyperselection status significantly influence maintenance strategy efficacy in mCRC. For left-sided, negative hyperselected patients, Panitumumab monotherapy may optimize efficacy while minimizing toxicity. Further investigation into the relative contribution of individual hyperselection parameters in this setting is warranted.

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Conflict of interest statement

Competing interests: AB: Stock and other ownership interests: BioNTech SE. Honoraria: Amgen. Research funding: Amgen (Inst). Travel, Accommodations, Expenses: Amgen. FM: Honoraria from Pierre Fabre and Servier; research grants from Incyte (to their institution); travel grants from Amgen and Pierre Fabre. AS: Honoraria: Roche, Servier, Taiho Pharmaceutical. Consulting or advisory role: Bristol Myers Squibb/Pfizer, Novocure. Travel, Accommodations, Expenses: Amgen, Roche, Lilly, Pfizer. SL: Participation in advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm, and Beigene; personal honoraria as invited speaker from Amgen, AstraZeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, and Servier; research funding (to their institution) from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier. AJK: No competing interests declared. CC: Advisory board or consultant role with Astra Zeneca, Bicara Therapeutics, BMS, GSK, Lilly, Merck, Mirati, MSD, Nordic Pharma, Roche, Pfizer, Pierre Fabre, Revolution Medicine, Rottapharm, Takeda, Tempus; Invited speaker with compensation for Amgen, Bayer, Merck Serono, MSD, Pierre Fabre Servier, Takeda; Research grants by Amgen, Merck, Pierre Fabre, Roche, Seagen (Pfizer), Servier, Tempus. SS: No competing interests declared. GR: No competing interests declared. DH: No competing interests declared. MP: No competing interests declared. AHSA: Honoraria: MSD. Travel, Accommodations, Expenses: Merck, BMS GmbH and Co. KG. CCP: No competing interests declared. AJ: No competing interests declared. PA: No competing interests declared. Annika Kurreck: Honoraria: Taiho Pharmaceutical, Amgen, Servier. Travel, Accommodations, Expenses: medac, Amgen, Servier. AAC: No competing interests declared. SS: Honoraria: Merck KGaA, Roche, Amgen, Servier, MSD, Pfizer, Pierre Fabre, Bristol Myers Squibb GmbH, Nordic Bioscience, AstraZeneca. Consulting or advisory role: Merck Kgaa, Roche, Amgen, Pierre Fabre, MSD, AstraZeneca, Servier, GlaxoSmithKline, Terumo, Nordic Bioscience, Seagen. Research Funding: Pierre Fabre (Inst), Roche Molecular Diagnostics (Inst), Merck Serono (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Merck KGaA, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Lilly, Takeda, Pierre Fabre, AstraZeneca. FP: Research funding (to their institution) from Lilly, Bristol-Myers Squibb, Incyte, AstraZeneca, Amgen, and Agenus; personal honoraria as an invited speaker from BeiGene, Daiichi Sankyo, Seagen, Astellas, Ipsen, AstraZeneca, Servier, Bayer, Takeda, Johnson & Johnson, Bristol-Myers Squibb, MSD, Amgen, Merck Serono, Pierre Fabre; and advisory or consultancy fees from Bristol-Myers Squibb, MSD, Amgen, Pierre Fabre, Johnson & Johnson, Servier, Bayer, Takeda, Astellas, GSK, Daiichi Sankyo, Pfizer, BeiGene, Jazz Pharmaceuticals, Incyte, Rottapharm, and Merck Serono. DPM: Honoraria: Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Merck Sharp and Dohme, Pierre Fabre, Onkowissen, Sanofi, Lilly, AstraZeneca/MedImmune, Incyte, Takeda. Consulting or advisory role: Merck Serono, Amgen, Merck Sharp and Dohme, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQVIA, Onkowissen. Research funding: Amgen (Inst), Servier (Inst). Travel, Accommodations, Expenses: Amgen, Merck Serono, Servier. AR: Honoraria for speaker bureau or advisory board participation from Servier and MSD. Ethics approval and consent to participate: The study protocols and its amendments were approved by an independent institutional review board or ethics committee at each study site. The study was conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written, informed consent. This secondary analysis is part of an IPD pooled analysis study and was approved by the ethical committee of Fondazione IRCCS Istituto Nazionale dei Tumori (Identifier: INT 99/22).

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